Can TNF-α boost regulatory T cells?

Abstract

Deleterious immune responses that cause autoimmune diseases such as type 1 diabetes are normally kept in check by a myriad of mechanisms. Among these, protection mediated by CD4+Foxp3+ Tregs constitutes an essential pathway. Much work over the past decade aimed to understand how Tregs affect immune responses triggered by effector T cells (Teffs), but less is known about how Teffs affect Tregs. In this issue of the JCI, Grinberg-Bleyer et al. report the clearest example thus far regarding this important aspect of Treg biology. They find that in mice, sustained protection from diabetes by Tregs is dependent on Teffs and partially dependent on TNF-α, a cytokine traditionally considered proinflammatory.

Figure 1. Feedback control of Tregs by Teffs.

The drawing illustrates how Teffs help Tregs control themselves, as suggested by the data generated by Grinberg-Bleyer et al. (6). Pathogenic T cells infiltrate and inflame the tissue. Teffs produce inflammatory cytokines such as TNF-α (which can also be produced by activated dendritic cells and macrophages) that can act on Tregs to promote their proliferation and expansion. Tregs can now outcompete the Teffs and also secrete antiinflammatory cytokines that will hamper the proliferation of Teffs. Decreased proliferation of Teffs will limit ongoing inflammation. An alternative pathway in which antigen presentation directly to Tregs may lead to their expansion and subsequent control of inflammation is highlighted in the gray box.